The broad, LONG TERM OBJECTIVE is to improve the therapy of ethanol (EtOH) induced diseases of excitable tissue via better insight into mechanisms. As many EtOH studies can't be done accurately in man, an animal model is needed. Our MODEL is cat esophagus since it is: a) similar to man's; b) accessible for repeated physiologic studies; c) one in which biochemical & physiological changes can be correlated d) an organ for simultaneously studying: smooth muscle (lower esophagus[LE]), striated muscle (upper esophagus[UE]), & specialized smooth muscle (lower esophageal sphincter [LES]]). We characterized EtOH-induced esophageal dysmotility (EIED) in man, developed an animal model for it, & studied mechanisms. In men, acute EtOH decreases LES pressure (LESP) & LE pressure (LEP). But, during withdrawal from EtOH, LESP & LEP increased. In cats, parallel findings were noted in LES & LE in males only, suggesting that female sex hormones attenuate EtOH's chronic effects. UE pressure (UEP) responded differently than LEP in cats: acute EtOH had no effect on UEP while UEP rose during both chronic EtOH & withdrawal. Of two popular hypotheses for chronic EtOH's effects, up-regulation of neurotransmitter receptors, or perturbation of Ca2+ regulation, our data failed to support the first. The second, which now needs to be tested, is plausible since: 1) cytosolic Ca2+ concentration ([Ca2+]i) is critical to excitable tissue function; 2) EtOH disrupts Ca2+ regulation in brain & vascular smooth muscle; 3) acute EtOH decreases Ca2+ influx into LES & LE slices but only minimally increases influx into UE (our data). HYPOTHESIS: 1. During Acute EtOH: [a] in smooth muscle, a drop in Ca2+ influx & [Ca2+]i lowers LESP & LEP. [b] in striated muscle, a rise in Ca2+ influx occurs, but [Ca2+]i fails to increase sufficiently to elevate UEP. 2. During Chronic EtOH: [a] in smooth muscle, Ca2+ channels up-regulate so that in withdrawal, elevated [Ca2+]i raises LESP & LEP. [b] in striated muscle, Ca2+ influx now increases sufficiently to increase [Ca2+]i & UEP rises. {{ In 1 & 2 above, muscle is EtOH's primary target.}} 3. In females, sex hormones attenuate the EtOH-induced increases in [Ca2+]i, which results in smaller pressure changes in withdrawal.
Our SPECIFIC AIMS are to evaluate: 1. The effect of acute EtOH on [a] muscle contractions ({{in vitro strips & dispersed muscle cells}}; in vivo motility) [b] Ca2+ parameters in LES, LE & UE: [i]45Ca2+ influx into esophageal slices {{ or cells }}; [ii] [Ca2+]i in cells using fluorescent dyes. [iii] [3H]nitrendipine binding to Ca2+ channels in slices. 2. The effect of chronic EtOH on LES, LE & UE as in Aim #1. 3. The role of female sex hormones in EIED by measurement of [a] esophageal motility in alcoholic women & ovariectomized cats; [b] the effect of female sex hormones on {{muscle contraction}} & Ca2+ parameters in cells, slices & strips. {{ In all Aims, Ca2+ data will be correlated with muscle contraction data}}. These experiments should not only reveal the mechanism for EIED but also, confirm that functional changes in excitable tissue correlate with altered C12+ regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007255-05
Application #
3110981
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1987-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Keshavarzian, A; Holmes, E W; Patel, M et al. (1999) Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 94:200-7
Ashrani, A; Keshavarzian, A; Jacyno, M et al. (1997) Are dipyridamole (sensitive) calcium channels present in esophageal smooth muscle? Life Sci 60:PL423-30
Keshavarzian, A; Muska, B; Sundaresan, R et al. (1996) Ethanol at pharmacologically relevant concentrations inhibits contractility of isolated smooth muscle cells of cat esophagus. Alcohol Clin Exp Res 20:180-4
Fields, J Z; Jacyno, M; Wasyliw, R et al. (1995) Ethanol inhibits contractility of esophageal smooth muscle strips. Alcohol Clin Exp Res 19:1403-13
Keshavarzian, A; Zorub, O; Sayeed, M et al. (1994) Acute ethanol inhibits calcium influxes into esophageal smooth but not striated muscle: a possible mechanism for ethanol-induced inhibition of esophageal contractility. J Pharmacol Exp Ther 270:1057-62
Keshavarzian, A; Fields, J Z; Vaeth, J et al. (1994) The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol 89:2205-11
Fields, J Z; Turk, A; Durkin, M et al. (1994) Increased gastrointestinal symptoms in chronic alcoholics. Am J Gastroenterol 89:382-6
Keshavarzian, A; Polepalle, C; Iber, F L et al. (1992) Secondary esophageal contractions are abnormal in chronic alcoholics. Dig Dis Sci 37:517-22
Keshavarzian, A; Gordon, J H; Willson, C et al. (1992) Chronic ethanol feeding produces a muscarinic receptor upregulation, but not a muscarinic supersensitivity in lower esophageal sphincter muscle. J Pharmacol Exp Ther 260:601-7
Keshavarzian, A; Urban, G; Sedghi, S et al. (1991) Effect of acute ethanol on esophageal motility in cat. Alcohol Clin Exp Res 15:116-21

Showing the most recent 10 out of 17 publications